ni hms 273343

Update On Stem Cell Therapy For Cerebral Palsy

James E Carroll1 and Robert W Mays2James E Carroll: [email protected] College of Georgia, Neurology, BG2000H, 1446 Harper Street, Augusta, GA 30912 USA2Athersys, Inc., Regenerative Medicine, 3201 Carnegie Avenue, Cleveland, 44115-2634 USA

AbstractIntroductionDue to the publicity about stem cell transplantation for the treatment of cerebralpalsy, many families seek information on treatment, and many travel overseas for celltransplantation. Even so, there is little scientific confirmation of benefit, and therefore existingknowledge in the field must be summarized.

Areas coveredThis paper addresses the clinical protocols examining the problem, types ofstem cells available for transplant, experimental models used to test the benefit of the cells,possible mechanisms of action, potential complications of cell treatment, and what is needed in thefield to help accelerate cell-based therapies.

Expert OpinionWhile stem cells may be beneficial in acute injuries of the central nervoussystem, the biology of stem cells is not well enough understood in chronic injuries or disorderssuch as cerebral palsy. More work is required at the basic level of stem cell biology, in thedevelopment of animal models, and finally in well-conceived clinical trials.

KeywordsAnimal models; cerebral palsy; embryonic stem cells; induced pluripotent stem cells;mesenchymal cells; multipotent adult progenitor cells; stem cells; transplantation

1. IntroductionCerebral palsy is a heterogeneous group of conditions, defined as non-progressive motordisability due to an abnormality of the cerebral hemispheres. While a small proportion ofpatients with cerebral palsy have as their cause a perinatal hypoxic-ischemic insult, mosthave acquired cerebral palsy due to the presence of one of a wide variety of other illnesses,such as developmental brain abnormalities, genetic conditions, traumatic or infectiousdisorders. Furthermore, insults may occur at different times during gestation, resulting ineven more variation in pattern and causation. This heterogeneity in cause makes theassessment of any treatment fraught with considerable difficulty.

Parents, on the other hand, focus on the condition of cerebral palsy and seek treatment basedon that terminology. Patoine, in a recent editorial [1], described the pressures of a supposedMiracle Cure supplied by stem cells influencing the behavior of parents of children withcerebral palsy. The United Cerebral Palsy Foundation states that there are 800,000 children

Declaration of interestJ Carroll has received funding from Associazione Assistenza Figli Inabili Banca dItalia, Cord Blood Registry, NINDS5R42NS55606,RW Mays is an employee and stake holder at Athersys, Inc

NIH Public AccessAuthor ManuscriptExpert Opin Biol Ther. Author manuscript; available in PMC 2012 April 1.

Published in final edited form as:Expert Opin Biol Ther. 2011 April ; 11(4): 463471. doi:10.1517/14712598.2011.557060.

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-PA Author Manuscript

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and adults in the United States with cerebral palsy. The Centers for Disease Controlestimates that about 10,000 babies are born each year with cerebral palsy. Improvements inthe care of neonates have done little to alter the percentage of children with cerebral palsy.In fact, the increased survival of vey low birth weight infants has contributed to sustainingof the present occurrence rate [2]. Thus, the issue of stem cells as a potential treatment forcerebral palsy has assumed a disproportionally elevated position among parents of childrenwith cerebral palsy.Seven years ago we presented in this journal the state of stem cellresearch in cerebral palsy [3]. While there has been definite progress in the scientific studyof multiple types of stem cells, particularly the discovery of induced pluripotent stem cells(iPS cells), relevant animal models for cerebral palsy are still lacking in critical factors.Consequently, the progress with the initiation of cell based clinical trials for treatment ofcerebral palsy has been limited.

An additional problem is the timing of treatment. In order to be effective for most patientswith cerebral palsy, the treatment will need to address an established or longstanding brainabnormality. But as we accumulate more information about the potential mechanisms ofaction of stem cells in brain injury, we are led to the conclusion that stem cells are muchmore likely to be effective in the acute situation rather than long into the course of a chronicdisability. However, it is possible that stem cells could act favorably in a chronic injury byreplacing nerve cells, with even a small replacement being significant, by making existingconnections more effective, or by promoting blood vessel regeneration.

The purpose of this article is to present the current state of stem cell transplantation forcerebral palsy patients. We will review the current efforts with patients, the types of cellsthat might be used, the experimental basis for the treatment, animal models for cerebralpalsy, the possible mechanisms for therapeutic success, the need for additional work, and thepotential for harm.

2. Stem Cell Trials for Cerebral Palsy Two US trials

Several foreign trials

There are two on-going US trials (Duke University and the Medical College of Georgia)listed in ClinicalTrials.gov [4] testing the safety and efficacy of autologous umbilical cordblood for cerebral palsy. These trials are obviously dependent upon the fact that someparents chose to preserve their childs umbilical cord blood at the time of birth. The fact thatthe cells are autologous gives a significant safety margin to the trials, which otherwise mightnot have been allowed to proceed. Given that the parents have a strong commitment to stemcell therapy and enter the trials only because they know their children will receive the cells,both these trials are double-blinded with a crossover treatment protocol. The crossoverallows the children to receive their cells at some point in the study. The trials attempt to paredown the long list of causes for cerebral palsy by having extensive exclusion criteria, suchas athetoid cerebral palsy, autism, hypsarrthymia, intractable epilepsy, progressiveneurological disorder, HIV infection, extreme microcephaly, known genetic disorder,obstructive hydrocephalus, significant defect of brain development, chromosomal disorder,presence of major congenital anomaly, or severe intrauterine growth retardation. One of themain justifications for these trials is the need to investigate the efficacy of this treatment inthe face of ongoing clinical usage of the treatment. Currently there are no US trials forcerebral palsy dealing with allogeneic cell therapies.

While hypoxic-ischemic injury is a clear cut and easily definable cause of cerebral palsy andpossibly the most potentially open to treatment, this cohort of patients is in the minority. The

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current US trials attempt to focus on this group. Perhaps fewer than 100,000 of the 800,000individuals with cerebral palsy have hypoxic-ischemic injury as their cause.

A third trial listed in ClinicalTrails.gov [4] is conducted by the Sung Kwang MedicalFoundation in the Republic of Korea. This study is double-blinded, randomized withplacebo control using allogeneic umbilical cord blood in combination with erythropoietin.The three arms of the study are: 1) umbilical cord blood, erythropoietin, and rehabilitation,2) erythropoietin and rehabilitation, and 3) rehabilitation only. This study employsimmunosuppression in order to allow for the use of the allogeneic cells.

A fourth trial listed in ClinicalTrials.gov [4] is active but not recruiting (HospitalUniversitario, Monterrey, Mexico). In this trial the patients are given granulocyte colonystimulating factor (G-CSF in order to stimulate their bone marrow to produce stem cells,bone marrow is harvested, and CD 34+ cells are purified and delivered via the intrathecalroute.

Outside the US, there are a number of facilities which offer treatment with various types ofstem cell preparations for cerebral palsy. These facilities are not conducting formal clinicaltrials. Stem cells offered from these companies or institutions are usually autologous adultstem cells prepared from the patients own tissue, usually bone marrow. The specific detailsof the preparation methods are generally not available. The cells are delivered eitherintravenously or into the cerebrospinal fluid. Often multiple administrations arerecommended.

3. Potential Cell Sources Mesenchymal stem cells

CD34 cells

Umbilical cord blood

Multipotent adult progenitor cells

Induced pluripotent stem cells

Oligodendrocyte progenitor cells

Embryonic stem cells

Fetal stem cells

There are many potential cell sources which have been used for experimental treatmentprotocols in animal models. The studies employ either direct implantation into brainparenchyma or, more commonly, intravenous injection. We recently reviewed the variouscell sources [5].

3.1-Mesenchymal Stem Cells (MSCs)Mesenchymal stem cells (MSCs) are bone marrow stromal cells, comprised of a mixture ofcell types, capable of supporting hematopoiesis along with the capability to differentiate intomultiple cell types. While bone marrow is considered the primary source of MSCs, they arealso found in human umbilical cord blood and to a lesser degree in other tissues. MSCs aregenerally isolated based on their preferential attachment to tissue culture plastic. The cellsare fibroblast- like and possess the ability for self renewal. Most of the adult stem cellscurrently studied share some similarities with MSCs.



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In all pre-clinical cerebral palsy studies to date testing MSCs, the cells have beenadministered in the short term [6,7,8,9], with the longest period being one month after injury[10]. The benefit is noted both with intravenous and intracerebral transplantation. Themechanism of cell action is unknown, but does not appear to be neuronal cell replacement.However, the treatment appears to lead to sparing of intrinsic cells. In a primate model, Li etal [11] reported that the cell transplantation resulted in up-regulation of interleukin-10expression. In association they found a decrease in neuronal apoptosis and astroglial activityin the peri-ischemic area. The number of proliferating cells in the subventricular zone wasalso increased.

3.2-CD34 CellsCD34 cells are found in umbilical cord blood and bone marrow. They represent a smallsubset of MSCs. These cells are isolated based on the presence of a transmembraneglycoprotein as their surface characteristic. Clinical trials are underway in stroke patients[4].

3.3-Umbilical Cord BloodUmbilical cord blood (UCB) is currently a popular source of adult stem cells being tested asa therapy for disease and injury. Numerous private and public banks have arisen in the USand other parts of the world. The collection of umbilical cord blood is somewhatcontroversial in that various organizations, including the American Academy of Pediatrics[12], have questioned the utility of the collection and preservation in private banks. Theseconcerns are based on the contention that there are few, if any, proven autologous therapies.To date, the main usage of these cells has been treatment of childhood diseases of the blood,although their experimental use for the treatment of cerebral palsy is currently underinvestigation. The minimum necessary dosage of cells for cell engraftment is usuallyconsidered to be 1 107 cells per kilogram. This includes the total nucleated cell fractionand not just stem cells. Thus, the child will outgrow the available dose of autologous cellsobtained at birth and available for transplant at a later date. Should autologous UCB befound efficacious for the treatment of acquired disorders, however, their usage wouldbecome wide spread.

UCB has been used experimentally in brain injury models. Benefit of the treatment has beenshown in a neonatal hypoxic-ischemic rat model [13], adult rat stroke models [14,15,16],and a rat traumatic brain injury model [17]. On the other hand, Makinen et al [18] did notfind benefit with UCB in a rat stroke model. These were all acute studies.

3.4-Multipotent Adult Progenitor CellsMultipotent adult progenitor cells (MAPC) (Athersys, Inc) are derived from bone marrow aswell as other tissue sources [19,20]. The phenotype consists of CD13+ Flk1dim, c-kit,CD44, CD45, MHC class I, and MHC class II. These cells differentiate intomesenchymal cells, but also cells with visceral mesoderm, neuroectoderm and endodermcharacteristics in vitro. They proliferate without senescence or loss of differentiationpotential. We have used these cells in a rat model of neonatal hypoxic-ischemic injury,where cell administration results in improvement in behavioral outcome and neuronalsparing as determined by histology. We observed benefit in an acute model via bothintracerebral and intravenous transplantation routes [21]. This was an important experimentin that we were able to show the efficacy of a safe and practical method of administration,i.e. intravenous. While some of the transplanted cells survived, and even displayed neuronalmarkers, the chief restorative feature was enhanced survival of endogenous neurons. Wespeculated this process was mediated by trophic factors, which would be most efficacious in



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the acute situation and perhaps less so in a chronic injury, as would be the case for cerebralpalsy.

Mays et al [22] reported recent data from our group in a rat model of ischemic stroke. Wedemonstrated that immunosuppression was not required for allogeneic or xenogeneic cellmediated benefit. The studies noted that improvement with MAPC administration persistedat least as long as six months following acute treatment. Based on histological data, it wasconcluded that MAPC do not exert their benefit via cell replacement but more likely bytrophic mechanisms. All of our work with MAPC is in acute studies, and once again weneed to show improvement in a chronic injury model in order to supply pre-clinical evidencethat would apply to cerebral palsy.

3.5-Induced Pluripotent Stem Cells Cells (IPS Cells)Induced Pluripotent Stem Cells (iPS Cells) are now considered to be a substitute forembryonic stem cells [23]. The use of iPS Cells has not yet been reported in any preclinicalmodel of brain injury. It seems that the cells may be an ideal source for tissue repair, as theycan be prepared from the patients own fibroblasts, eliminating considerations of rejection.However, there are a number of hurdles which will need to be cleared before this cell typewould be available for clinical usage. First, the safety of the cells will need to be amplydemonstrated in animal models. Do the cells form tumors? Are the viral agents used in thepreparation of the cells a danger to the recipient? Are the cells effective in animal models?Robbins et al [24] reviewed the use of these cells for transplantation and concluded thatreprogramming efficiency and safety considerations would need to be addressed before theinitiation of clinical trials. Thus, while iPS Cells seem quite promising, much work remainsto be done at the basic translational science level before they can move into the clinic.

3.6-Oligodendrocyte Progenitor CellsOligodendrocyte progenitor cells (OPC) may be derived from fetal brain tissue [25],embryonic stem cells, or iPS cells, the latter two via cell differentiation protocols. Onceagain the problem in relation to the chronic nature of cerebral palsy is that the models ofinjury utilized in experimental animals are acute. OPC derived from human embryonic stemcells demonstrated some amelioration of function in rats undergoing traumatic spinal cordinjury [26,27]. Keirstead et al [28] used human embryonic stem cell-derived OPC in a ratmodel of spinal cord injury and compared the cells in an acute model versus a chronicmodel. Animals receiving the transplant seven days after the injury showed remyelinationand improved motor ability compared to untreated animals; however the animals treated 10months after the injury demonstrated no statistical improvement over control animals. Thisstudy underlines the potential difficulty of developing effective therapeutics in the chronicinjury setting of the central nervous system.

Tokumoto et al [29] evaluated the ability of iPS cells derived from mouse embryonicfibroblasts to differentiate into oligodendrocytes and compared this with the differentialability of mouse embryonic stem cells (ESC). They found that intracellular factors inhibitedthe differentiation of iPS cells into mature oliogodendrocytes.

3.7-Embryonic Stem CellsEmbryonic stem cells (ESC) are certainly the most controversial type of stem cells. They arederived from embryos and generally require the destruction of that embryo. Consequently,there remain abiding ethical concerns about their use. In addition, the proliferative capacityof the cells and their potential for differentiation into many cell types makes the possibilityof tumor formation quite real. Given that children receiving the cells would have many yearsin front of them, there would be ample time for tumor formation to occur.



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The animal models examined with ESCs are all in acute injuries. Zhang et al [30] studiedtransplantation in a rat stroke model 24 hours after the injury and found favorable post-implantation histological changes with survival of the transplanted cells, their migration anddifferentiation toward neural cell types. Liu et al [31] reported that mesenchymal cellsderived from ESCs lessened rat infarction volume, differentiated into neuronal andendothelial cells, and improved functional outcome when injected intravenously. Ma et al[32] showed that embryonic-derived stem cells possessed the ability to migrate into theinjury site and improve learning ability and memory fully eight months after the injury.Even though the benefit of the ESCs was long-lasting, the treatment was delivered in theacute phase after injury.

3.8-Fetal Stem CellsFinally, stem cells can be collected from fetal tissue. While the utility of these cells have notbeen widely explored in injury models, there are indeed indications of their potential. Aftabet al [33] demonstrated that retinal progenitor cells from donor tissue of 1618 weeksgestational age were able to integrate inot host retina and express rhodopsin. In otherexperiments cells from fetal brain transplanted acutely after hemorrhagic stroke displayedneuroprotecting anti-inflammatory capacity [34].

4. Experimental Models Neonatal rat hypoxic-ischemic model

Lipopolysaccharide plus hypoxia-ischemia

Perinatal rabbit model

Neonatal sheep model

Neonatal primate model

Lack of chronic model

While cerebral palsy is caused by a number of conditions of which brain injury is a minorcomponent, the models for cerebral palsy are generally based on some type of brain injury.The ideas for various therapies, therefore, are predicated on the notion that we can reversethe effects of the injury. Even though this may be the case for an acute injury, this themedoes not apply to the many children with cerebral palsy whose condition arises fromabnormalities of brain development. Our discussion in regard to the models of cerebral palsyis confined to the types of cerebral palsy arising from injury.

Johnston et al [35] have recently reviewed the available animal models and concluded thatnone are fully adequate.

The Rice-Vannucci model [36] which combines unilateral carotid artery ligation withhypoxia in 7-day-old rat pups has been used for numerous studies on the cause and treatmentof brain injury in the neonatal animal. These are studies of acute injury.

The use of lipopolysaccaharide as a pretreatment to induce vulnerability to hypoxic-ischemic insult has added the important aspect of prenatal infection to the examination ofthe problem [37]. Girard et al [38] showed that the combination of lipopolysaccharideexposure and hypoxic-ischemic injury in rats mimicked the motor deficits andneuropathological lesions seen in very premature infants. Their motor deficits were morepersistent making this one of the more promising models for chronic injury.



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In view of the frequency of cerebral palsy occurring related to prematurity, the importanceof white matter injury is an important consideration. Periventricular leukomalacia is themost frequent lesion in these patients. White matter lesions are not well-seen in rodentmodels, as the rodents have comparatively little white matter. In order to mimic the lesionseen in premature infants, several larger animal models have been developed whichdemonstrate white matter injury [35].

The perinatal rabbit model of cerebral palsy probably best fits the criterion of an injuryproducing motor disability. This model is produced by uterine ischemia [3942] or byintrauterine administration of endotoxin [43]. However, these models do not appear tosupply the chronic or long-lasting deficit we believe is required for satisfactory assessment.

Larger animal models, such as the sheep [44] or baboon [45], better reproduce the pathologyseen in human infants. The pre-term baboon mimics the white matter neuropathology seenin premature human infants [45]. The expense of these methods, however, appears to beprohibitive for the number of animals required for an adequately powered study.

One of the central problems in the development of stem cell therapies for cerebral palsy isstill the lack of satisfactory experimental models. Ideally the model should includeimpairment of movement as a result of a brain injury. Secondly, the model should be one ofchronic rather than acute injury. The more critical of these two factors actually is the needfor a chronic or long-lasting injury. There have been numerous experimental treatments ofacute injury models that have demonstrated success but none that have shown efficacy in atrue, chronic model of injury. We and other investigators have shown that acute injuries aresubject to repair by cell therapy, while the problem of chronic injury has been more resistantor neglected. The important feature that needs to be demonstrated is the capacity of the celltherapy to repair a chronic injury of any type. The type or location of the brain injury iscomparatively less important than the need for a persistent, abnormal behavioral syndromeof some type in the animal.

5. Possible Mechanisms of Action Neuronal cell replacement

Astrocyte, microglial cell replacement

Blood vessel regeneration

Protection of intrinsic cells

Blockade of splenic release of inflammatory cells

One of the main ideas inherent in stem cell transplantation for cerebral palsy is that the stemcells would replace the cells of the damaged nervous system. Most reports dealing with adultstem cells show only a minimal survival of the transplanted cells with few, if any, of thesecells displaying markers/functionality of nervous tissue [21,46,47]. It does not appear thatreplacement alone would be sufficient to account for improvement in the experimentalsituation. While embryonic or iPS cells may have somewhat greater potential for suchreplacement and transformation, the number of cells undergoing this process is quite limitedin vivo. Even though there may be some replacement by transplanted cells, the cells often donot develop normal processes and may not function in neuronal circuitry [48]. Thus, cellreplacement as an explanation for any improvement in the models is unlikely to be the casegiven the current state of our knowledge of the cell biology of stem cells.

Another possibility is that the transplanted cells differentiate into astrocytes [48] ormicroglia. How this would assist in functional recovery is unclear.



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Bone marrow derived cells may participate in blood vessel regeneration by promotingadhesion of CXCR4-positive cells onto vascular endothelium [49], recruitment ofendothelial progenitor cells [50], and in the formation of periendothelial vascular cells [51].Borlongan et al [52] have demonstrated that crude bone marrow may form endothelial cellsin an animal model of stroke.

A fourth set of ideas related to benefit is that the transplants induce a greater survival ofintrinsic cells. We reported this phenomenon in our neonatal hypoxic-ischemic model inanimals treated with MAPC [21]. Mahmood et al [53] used MSC injection to demonstratethat transplanted cells increased the expression of nerve growth factor and brain-derivedneurotrophic factor after traumatic injury. This idea, for which the evidence seems strong,tends to restrict the benefit of stem cell transplantation to the acute post-injury period.

Another possible mechanism of benefit is the effect of adult stem cells on splenic functionduring acute brain injury. In a stroke model Vendrame et al showed that UCB lessened thesplenic release of inflammatory cells and thereby protected the brain [54]. In support of thisconcept Walker et al [55] demonstrated that the intravenous injection of MAPC after traumablocked the normal splenic response to injury and improved outcome. These reportssupported the idea that the spleen plays a role in adversely increasing the blood brain barrierpermeability and that the splenic response is blocked by adult stem cell therapy. Once again,this is a benefit only for the acute situation.

6. Risks of Treatment Risks of allogeneic cells

Various causes of encephalopathy

Transmission of viral infection

The risks of stem cell therapy occur primarily with allogeneic transplants, which expose therecipient to graft versus host disease. Most reports of complications are in childrenundergoing hematopoietic stem cell transplantation for malignancies. These complicationsmay relate in part to the fact that these children received radiation therapy, chemotherapy, orimmunosuppressive medications in addition to the stem cell transplant. Herpes orcytomegalovirus infections may occur in these patients [56]. A variety of other medicalcomplications are also reported in similar groups of patients [57,58]. Woodward et al [59]reviewed 405 patients who received hematopoietic stem cell transplantation for a variety ofdisorders. Twenty-six patients experienced some type of encephalopathy due to infection,organ failure, medication reaction, seizures, acute disseminated encephalomyelitis,thrombotic thrombocytopenic purpura, or stroke.

Herpes virus-6 encephalitis is also reported as a complication of unrelated umbilical cordtransplant [60].

Clearly, we should not consider stem cell transplantation, particularly allogeneic, to be abenign procedure. Autologous transplantation may incur some of the same risks, particularlyas the patients may be exposed to chemotherapy or infectious agents. The complicationsmay relate significantly to the treatment accompanying transplantation or the site to whichthe transplant is delivered, such as into the cerebrospinal fluid.

While adult stem cell transplants have been carried out in large numbers of cerebral palsypatients outside the US, there is no systematic reporting of complications. One would thinkthat the route of administration, i.e. intravenous versus directly into the central nervoussystem, might be a key to the understanding of complications, but the reporting of routes and



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their complications are unavailable. Without question, the long term complications aresimply unknown.

7. Whats Needed Next Basic knowledge of stem cell biology

Satisfactory model of chronic injury

Multi-center trials with homogenous patient groups

We must have more knowledge of the biology and laboratory manipulation of the differenttypes of stem cells. This area must include more work in the area of cell differentiationstrategies. In addition we need to learn more about the effects of the various methods ofstimulating intrinsic neural proliferation.

A chronic, pre-clinical animal model is required for the study of the various competing cellstypes. The different cell types need to be compared in head-to-head competition.

Controlled clinical trials are needed. These should be conducted with very specificallydescribed patient groups, particularly more so than the current, on-going US trials. We mustrecognize that there are considerable differences among cerebral palsy patients, andtherefore the patients need to be carefully matched for each study. This type of trial couldonly be achieved in a coordinated multiple center paradigm.

8. ConclusionCurrent clinical trials in the use of stem cells for cerebral palsy are on-going and incomplete.While there are a number of different cell types that are potential candidates as treatments,none have been shown to be effective in chronic animal models. Furthermore, availableanimal models do not adequately mimic cerebral palsy. Risks of the treatment are reported.More work on understanding the underlying beneficial biology of stem cells and thedevelopment and validation of more relevant animal models is required.

9. Expert OpinionStem cell therapy for cerebral palsy remains a frustrating area. Considering all the publicityabout stem cells and the fact that cell therapy is widely available outside the US for a price,parents feel that surely the treatment must work. This view tends to be confirmed bypreclinical reports of benefit in animal models of acute injury. Anecdotal reports of success,of which there are many, contribute little toward clarifying any benefit, but neverthelessencourage parents of cerebral palsy patients to seek the unproven therapy. There is noevidence as yet that stem cell therapy works in a chronic model of injury, as would berelevant to cerebral palsy.

The problem remains difficult for several reasons: cerebral palsy is not a homogeneousdisease, our knowledge of stem cell biology is in its infancy, the pre-clinical models are farfrom ideal, and various preclinical trials show efficacy in acute models leading to falselyraised hopes.

We need a safe cell type that is effective in a chronic animal model of brain injury. Despiteclinical use of stem cell treatment for cerebral palsy in many sites outside the US, evidenceof efficacy in a chronic animal model will be necessary before a clinical trial will be allowedin the US using any type of allogeneic cell. We believe it would be inappropriate to conducta clinical trial for cerebral palsy using allogeneic cells without safety and efficacy data in achronic animal model.



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For the time being it may better to focus on the treatment of acute brain injuries with stemcells and thereby the improvement or prevention of cerebral palsy in this subset of patients.

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